Antimicrobial agents

ABSTRACT

Compounds of formula (I) and (IA) have antibacterial or antiprotozoal activity: formula (1) formula (2) wherein: Z represents a radical of formula N(OH)CH(═O) or of formula C(═O)NH(OH); R 1  represents hydrogen, methyl or trifluoromethyl, or, except when Z is a radical of formula N(OH)CH(═O), a hydroxy or amino group; R 2  represents a radical of formula R 10 —(X) n -(ALK) m — wherein R 10  represents hydrogen, or an optionally substituted c 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, aryl, or heterocyclyl group, ALK represents a straight or branched divalent C 1 -C 6  alkylene, C 2 -C 6 ?alkenylene, or C 2 -C 6  alkynylene radical, and may be interrupted by one or more non-adjacent NH—, —O— or S— linkages, X represents NH—, —O— or S—, and m and n are independently 0 or 1; R 3  represents hydrogen, C 1 -C 6 alkyl, or benzyl; and R 4  is as defined in the specification.

[0001] This invention relates to the use of hydroxamic acid and N-formylhydroxylamine derivatives as antibacterial and antiprotozoal agents, tonovel compounds within those classes, and to pharmaceutical andveterinary compositions comprising such compounds.

BACKGROUND OF THE INVENTION

[0002] In general, bacterial pathogens are classified as eitherGram-positive or Gram-negative. Many antibacterial agents (includingantibiotics) are specific against one or other Gram-class of pathogens.Antibacterial agents effective against both Gram-positive andGram-negative pathogens are therefore generally regarded as having broadspectrum activity.

[0003] Many classes of antibacterial agents are known, including thepenicillins and cephalosporins, tetracyclines, sulfonamides,monobactams, fluoroquinolones and quinolones, aminoglycosides,glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim andchloramphenicol. The fundamental mechanisms of action of theseantibacterial classes vary.

[0004] Bacterial resistance to many known antibacterials is a growingproblem. Accordingly there is a continuing need in the art foralternative antibacterial agents, especially those which have mechanismsof action fundamentally different from the known classes.

[0005] Amongst the Gram-positive pathogens, such as Staphylococci,Streptococci, Mycobacteria and Enterococci, resistant strains haveevolved/arisen which makes them particularly difficult to eradicate.Examples of such strains are methicillin resistant Staphylococcus aureus(MRSA), methicillin resistant coagulase negative Staphylococci (MRCNS),penicillin, quinolone or macrolide resistant Streptococcus pneumoniaeand multiply resistant Ent rococcus faecium.

[0006] Pathogenic bacteria are often resistant to the aminoglycoside,β-lactam (penicillins and cephalosporins), macrolide, quinolone andchloramphenicol types of antibiotic. The mechanism of resistance caninvolve the enzymatic inactivation of the antibiotic by hydrolysis,formation of inactive derivatives, mutation of the molecular targetand/or activation of transport pumps. The β-lactam (penicillin andcephalosporin) family of antibiotics are characterised by the presenceof a β-lactam ring structure. Resistance to this family of antibioticsin clinical isolates is most commonly due to the production of a“penicillinase” (β-lactamase) enzyme by the resistant bacterium whichhydrolyses the β-lactam ring thus eliminating its antibacterialactivity.

[0007] Recently there has been an emergence of vancomycin-resistantstrains of enterococci (Woodford N. 1998 Glycopeptide-resistantenterococci: a decade of experience. Journal of Medical Microbiology.47(10):849-62). Vancomycin-resistant enterococci are particularlyhazardous in that they are frequent causes of hospital based infectionsand are inherently resistant to most antibiotics. Vancomycin works bybinding to the terminal D-Ala-D-Ala residues of the cell wallpeptidoglycan precursor. The high-level resistance to vancomycin isknown as VanA and is conferred by genes located on a transposableelement which alter the terminal residues to D-Ala-D-lac thus reducingthe affinity for vancomycin.

[0008] In view of the rapid emergence of multidrug-resistant bacteria,the development of antibacterial agents with novel modes of action thatare effective against the growing number of resistant bacteria,particularly the vancomycin resistant enterococci and βlactamantibiotic-resistant bacteria, such as methicillin-resistantStaphylococcus aureus, is of utmost importance.

BRIEF DESCRIPTION OF THE INVENTION

[0009] This invention is based on the finding that certain hydroxamicacid and N-formyl hydroxylamine derivatives have antibacterial andantiprotozoal activity, and makes available new antibacterial andantiprotozoal agents. The compounds with which this invention isconcerned are antibacterial with respect to a range of Gram-positive andGram-negative organisms. They are characterised by the presence in themolecules of a backbone structure of formula (IB)

[0010] in which Z is a hydroxamic acid or N-formyl hydroxylamine groupand to which backbone a variety of substituent moieties are attached viathe bonds shown as intersected by wavy lines.

[0011] Although it may be of interest to establish the mechanism ofaction of the compounds with which the invention is concerned, it istheir ability to inhibit bacterial growth that makes them useful.However, it is presently believed that their antibacterial activity isdue, at least in part, to intracellular inhibition of bacterialpolypeptide deformylase (PDF; EC 3.5.1.31).

[0012] All ribosome-mediated synthesis of proteins starts with amethionine residue. In prokaryotes, the methionyl moiety carried by theinitiator tRNA is N-formylated prior to its incorporation into apolypeptide. Consequently, N-formylmethionine is always present at theN-terminus of a nascent bacterial polyleptide. However, most matureproteins do not retain the N-formyl group or the terminal methionineresidue. Deformylation is required prior to methionine removal, sincemethionine aminopeptidase does not recognise peptides with an N-terminalformylmethionine residue (Solbiati et al., J. Mol. Biol. 290:607-614,1999). Deformylation is, therefore, a crucial step in bacterial proteinbiosynthesis and the enzyme responsible, PDF, is essential for normalbacterial growth. The gene encoding PDF (def) is present in allpathogenic bacteria for which sequences are known (Meinnel et al., J.Mol. Biol, 266:93949, 1997). Although a deformylase homologue hasrecently been cloned from the mitochondria of human cells (Giglione et.el. EMBO Journal, 19, 5916-5929, 2000) it has not been shown to befunctional, and its relevance is unknown. Since a number of currentlyused antibiotics are known to act on both bacteria and mitochondria, PDFis still considered to be a target for antibacterial chemotherapy (for areview see Giglione et al., Mol Microbiol., 36:1197-1205, 2000).

[0013] The isolation and characterisation of PDF has been facilitated byan understanding of the importance of the metal ion in the active site(Groche et al., Biophys. Biochem. Res. Commun., 246:324-6,1998). TheFe²⁺ form is highly active in vivo but is unstable when isolated due tooxidative degradation (Rajagopalan et al., J. Biol. Chem.273:22305-10,1998). The Ni²⁺ form of the enzyme has specific activitycomparable with the ferrous enzyme but is oxygen-insensitive (Ragusa etal., J. Mol. Biol. 1998, 280:515-23, 1998). The Zn²⁺ enzyme is alsostable but is almost devoid of catalytic activity (Rajagopalan et al.,J. Am. Chem. Soc. 119:12418-12419, 1997).

[0014] Several X-ray crystal structures and NMR structures of E. coliPDF, with or without bound inhibitors, have been published (Chan et al.,Biochemistry 36:13904-9, 1997; Becker et al., Nature Struct. Biol.5:1053-8,1998; Becker et al., J. Biol. Chem. 273:11413-6,1998; Hao etal., Biochemistry, 38:4712-9, 1999; Dardel et al., J. Mol. Biol.280:501-13, 1998; O'Connell et al., J. Biomol. NMR, 13:311-24, 1999),indicating similarities in active site geometry to metalloproteinasessuch as thermolysin and the metzincins.

[0015] The substrate specificity of PDF has been extensively studied(Ragusa et al., J. Mol. Biol. 289:1445-57,1999; Hu et al., Biochemistry38:643-50,1999; Meinnel et al., Biochemistry, 38:4287-95, 1999). Theseauthors conclude that an unbranched hydrophobic chain is preferred atP1′, while a wide variety of P2′ substituents are acceptable and anaromatic amide substituent may be advantageous at the P3′ position.There have also been reports that small peptidic compounds containing anH-phosphonate (Hu et al., Bioorg. Med. Chem. Left., 8:2479-82, 1998) orthiol (Meinnel et al., Biochemistry, 38:4287-95, 1999; Huntingdon etal., Biochemistry, 39: 4543-51, 2000; Wei et al, J. Combinatorial Chem.,2: 650-57, 2000) metal binding group are micromolar inhibitors of PDF.Peptide aldehydes such as calpeptin (N-Cbz-Leu-norleucinal) have alsobeen shown to inhibit PDF (Durand et al., Arch. Biochem. Biophys.,367:297-302,1999). Recently, the naturally occurring hydroxamic acidantibiotic actinonin, for which the target of its antibacterial activitywas previously unknown, was shown to be a potent inhibitor ofpolypeptide deformylase (WO 99/39704, and Chen et al, Biochemistry, 39:1256-62, 2000). Examples of non-peptidic PDF inhibitors with carboxylicacid (Green et al., Arch. Biochem. Biophys. 375: 355-8, 2000; Jayasekeraet al., ibid., 381:313-6, 2000) or hydroxamic acid (Apfel et al., J.Med. Chem., 43: 2324-31, 2000) metal binding groups are also known.

[0016] It has been reported that PDF is present in eukaryotic parasitessuch as Plasmodium falciparum (Meinnel, Parasitology Today, 16: 165-8,2000). Those authors also found evidence for the presence of PDF inother parasites of humans, such as the kinetoplastid protozoan parasitesTrypanosoma brucei and Leishmania major. Based on these findings, it isanticipated that the hydroxamic acid and N-formyl hydroxylaminecompounds with which this invention is concerned have antiprotozoalactivity, and are useful in the treatment of malaria and other protozoaldiseases.

[0017] Several N-formyl hydroxylamine derivatives have previously beendisclosed. The pharmaceutical utility ascribed to them is usually theability to inhibit matrix metalloproteinases (MMPs) and in some casesrelease of tumour necrosis factor (TNF), and hence the treatment ofdiseases or conditions mediated by those enzymes, such as cancer andrheumatoid arthritis. Also, WO 97/38705 (Bristol-Myers Squibb) and arecent publication (Robl et al., Bioorg. Med. Chem. Lett., 10: 257-60,2000) disclose certain N-formyl hydroxylamine derivatives asenkephalinase and angiotensin converting enzyme inhibitors. Furthermore,patent publications WO 99/41232 (British Biotech) and WO 00/43001(British Biotech) respectively disclose the use of certain N-formylhydroxylamine derivatives as inhibitors of proliferation of rapidlydividing cells and in the treatment of inflammation.

[0018] U.S. Pat. No. 4,738,803 (Roques et al.) also discloses N-formylhydroxylamine derivatives as enkephalinase inhibitors and they areproposed for use as antidepressants and hypotensive agents.

[0019] Of the publications referred to above, it appears only U.S. Pat.No. 4,738,803 (Roques et al.) discloses N-formyl hydroxylaminederivatives of the type with which this invention is concerned, iehaving a molecular backbone of formula (IA) above.

[0020] Very many hydroxamic acid derivatives are known. Many have beendisclosed as having matrix metalloproteinase (MMP) inhibitory activity,and thus to be potentially useful for the treatment of diseases mediatedby MMPS, for example cancer, arthritides, and conditions involvingtissue remodelling such as wound healing, and restenosis. Others havebeen disclosed as inhibitors of other metalloenzymes such asenkephalinase, angiotensin converting enzyme and TNF converting enzyme.Publications relating to such hydroxamic acid derivatives include somewhich disclose hydroxamic acid compounds having the characteristicbackbone structure (IA) of the compounds with which this invention isconcerned. Such publications include the following: US-A-4,738,803(Roques et al.) WO 91/08737 (Fisons) EP-A-0513810 (Searle/Monsanto) WO96/39385 (Pfizer) WO 97/20824 (Agouron) WO 99/06041 (Celgene) WO99/06340 (Procter & Gamble) WO 99/19296 (Ono) WO 00/59865 (Ono)Fournie-Zaluski et. al. Int. J. Pept. Protein Res. (1989), 33(2), 146-53Burrell et. al. Clin. Sci. (1997), 93(1), 43-50.

[0021] Notwithstanding publications such as those mentioned above whichdisclose certain compounds of the type with which this invention isconcerned, it appears none have recognised or taught the use of thpresent compounds as antibacterial or antiprotozoal agents. Furthermore,it appears some of the compounds with which this invention is concernedare novel per se, particularly the N-formyl hydroxylamines.

[0022] Actinonin is a naturally occurring antibacterial agent having ahydroxamic acid group, and certain derivatives of actinonin are alsoknown to have. antibacterial activity. (see for example Bouboutou et al,Colloq. INSERM (1989)174 (Forum Pept. 2^(nd), 19, 3414; Lelevre et. al.Pathol. Biol. (1989), 37(1), 4346; Broughton et. al. J. Chem. Soc.Perkin Trans. 1 (1975) (9), 857-60). In the latter publication, ananalogue of actinonin with the central amide linkage reversed wassynthesised (compound 21, Table 2, page 859) but it lacked antibacterialactivity. Our copending International patent applications nos. WO99/39704, WO 99/59568, WO 00/35440, WO 00/44373, WO 00/58294 and WO00/61134 disclose that certain N-formyl hydroxylamine and hydroxamicacid derivatives have antibacterial activity. With the single exceptionof compound 21 of Broughton et. al. mentioned above, the compounds withwhich these publications are concerned do not have the characterisingbackbone (IA) of the present compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0023] According to the first aspect of the present invention there isprovided the use of a compound of formula (I) or (IA) or apharmaceutically or veterinarily acceptable salt, hydrate or solvatethereof in the preparation of a composition for treatment of bacterialor protozoal infections in humans and non-human mammals:

[0024] wherein:

[0025] Z represents a radical of formula —N(OH)CH(═O) or of formula—C(═O)NH(OH);

[0026] R₁ represents hydrogen, methyl or trifluoromethyl, or, exceptwhen Z is a radical of formula —N(OH)CH(═O), a hydroxy or amino group;

[0027] R₂ represents a radical of formula R₁₀—(X)_(n)-(ALK)_(m)— wherein

[0028] R₁₀ represents hydrogen, or a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, cycloalkyl, aryl, or heterocyclyl group, any of which may beunsubstituted or substituted by (C₁-C₆)alkyl-, (C₁-C₆)alkoxy, hydroxy,mercapto, (C₁-C₆)alkylthio, amino, halo (including fluoro, chloro, bromoand iodo), trifluoromethyl, cyano, nitro, oxo, —COOH, —CONH₂, —COOR^(A),—NHCOR^(A), —NR^(A)COR^(B), —CONHR^(A), —NHR^(A), —NR^(A)R^(B), or—CONR^(A)R^(B) wherein R^(A) and R^(B) are independently a (C₁-C₆)alkylgroup or R^(A) and R^(B) taken together with the atom(s) to which theyare attached form a 5, 6 or 7 membered ring and

[0029] ALK represents a straight or branched divalent C₁-C₆ alkylene,C₂-C₆ alkenylene, or C₂-C₆ alkynylene radical, and may be interrupted byone or more non-adjacent —NH—, —O— or —S— linkages,

[0030] X represents —NH—, —O— or —S—, and

[0031] m and n are independently 0 or 1;

[0032] R₃ represents hydrogen, C₁-C₆alkyl, or benzyl;

[0033] R₄ represents

[0034] (ii) aryl, heterocyclic, aryl(C₁-C₆alkyl)-, orheterocyclic(C₁-C₆alkyl)-, any of which may be unsubstituted orsubstituted by cycloalkyl, nonaromatic heterocyclyl, methylenedioxy orany of the substituents defined as permitted in R₁₀; or

[0035] (ii) a radical of formula —(CR₅R₆)—Y—R₇ wherein

[0036] R₅ represents hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆alkynyl,aryl, heteroaryl, cycloalkyl, aryl(C₁-C₆alkyl)- or hetroaryl(C₁-C₆alkyl)-, any of which may be unsubstituted or substituted byany of the substituents defined as permitted in R₁₀

[0037] R₆ represents hydrogen or fluoro,

[0038] R₇ represents aryl, heteroaryl, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂or C₁-C₆alkyl, any of which may be unsubstituted or substituted bycycloalkyl, non-aromatic heterocyclyl, methylenedioxy or any of thesubstituents defined as permitted in R₁₀, and

[0039] Y represents a bond, —(CH₂)—, —C(═O)—, —C(═S)— or —C(═N—OR₈)—wherein R₈ represents C₁-C₆ alkyl or benzyl.

[0040] In another aspect, the invention provides a method for thetreatment of bacterial or protozoal infections in humans and non-humanmammals, which comprises administering to a subject suffering suchinfection an antibacterially or antiprotozoally effective dose of acompound of formula (I) as defined above.

[0041] In a further aspect of the invention there is provided a methodfor the treatment of bacterial contamination by applying anantibacterially effective amount of a compound of formula (I) as definedabove to the site of contamination.

[0042] The compounds of formula (I) as defined above may be used ascomponent(s) of antibacterial cleaning or disinfecting materials.

[0043] To the extent that compounds of formula (I) do not form part ofthe state of the art, such compounds and their pharmaceutically orveterinarily acceptable salts, hydrates or solvates are also an aspectof the present invention. In particular, the invention includes

[0044] (a) compounds of formula (I) above wherein Z represents a radicalof formula —N(OH)CH(═O), and R₄ represents aryl or heterocyclic, eitherof which may be unsubstituted or substituted by cycloalkyl, non-aromaticheterocyclyl, methylenedioxy or any of the substituents defined aspermitted in R₁₀; and

[0045] (b) compounds of formula (I) above wherein Z represents a radicalof formula —N(OH)CH(═O), and R₄ represents aryl(C₁-C₆alkyl)- orheterocyclic(C₁-C₆alkyl)-, either of which may be unsubstituted orsubstituted by cycloalkyl, non-aromatic heterocyclyl, methylenedioxy orany of the substituents defined as permitted in R₁₀ EXCEPT THAT the—(C₁-C₆alkyl)- radical in the aryl(C₁-C₆alkyl)- orheteroaryl(Cl-C6alkyl)- group may not be substituted by oxo; and

[0046] (c) compounds of formula (I) above wherein Z represents a radicalof formula —N(OH)CH(═O), and R₄ represents a radical of formula—(CR₅R₆)—Y—R₇ wherein

[0047] R₅ represents hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆alkynyl,aryl, heteroaryl, cycloalkyl, aryl(C₁-C₆alkyl)- orheteroaryl(C₁-C₆alkyl)-, any of which may be unsubstituted orsubstituted by or any of the substituents defined as permitted in R₁₀

[0048] R₆ represents hydrogen or fluoro,

[0049] R₇ represents aryl, heteroaryl, or C₁-C₆alkyl, any of which maybe unsubstituted or substituted by cycloalkyl, non-aromaticheterocyclyl, methylenedioxy or any of the substituents defined aspermitted in R₁₀, and

[0050] Y represents —(CH₂)—, —C(═O)—, —C(═S)— or —C(═N—OR₈)— wherein R₈represents C₁-C₆ alkyl or benzyl; and

[0051] (d) compounds of formula (I) above wherein Z represents a radicalof formula —N(OH)CH(═O), and R₄ represents a radical of formula—(CR₅R₆)—Y—R₇ wherein

[0052] R₅ represents hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆alkynyl,aryl, heteroaryl, cycloalkyl, aryl(C₁-C₆alkyl)- orheteroaryl(C₁-C₆alkyl)-, any of which may be unsubstituted orsubstituted by or any of the substituents defined as permitted in R₁₀

[0053] R₆ represents hydrogen or fluoro,

[0054] R₇ represents —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂ either of whichmay be unsubstituted or substituted by cycloalkyl, non-aromaticheterocyclyl, methylenedioxy or any of the substituents defined aspermitted in R₁₀ and

[0055] Y represents —(CH₂)—, —C(═O)—, —C(═S)— or —C(═N—OR₈)— wherein R₈represents C₁-C₆ alkyl or benzyl

[0056] PROVIDED THAT when R₆ is hydrogen then Y is not —C(═O)—.

[0057] On the hypothesis that the compounds (I) act by inhibition ofintracellular PDF, the most potent antibacterial effect may be achievedby using compounds which efficiently pass through the bacterial cellwall. Thus, compounds which are highly active as inhibitors of PDF invitro and which penetrate bacterial cells are preferred for use inaccordance with the invention. It is to be expected that theantibacterial potency of compounds which are potent inhibitors of thePDF enzyme in vitro, but are poorly cell penetrant, may be improved bytheir use in the form of a prodrug, ie a structurally modified analoguewhich is converted to the parent molecule of formula (I), for example byenzymic action, after it has passed through the bacterial cell wall. Thesame is true in the case of protozoa.

[0058] As used herein the term “(C₁-C₆)alkyl” means a straight orbranched chain alkyl moiety having from 1 to 6 carbon atoms, includingfor example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, n-pentyl and n-hexyl.

[0059] As used herein the term “divalent (C₁-C₆)alkylene radical” meansa saturated hydrocarbon chain having from 1 to 6 carbon atoms and twounsatisfied valencies.

[0060] As used herein the term “(C₂-C₆)alkenyl” means a straight orbranched chain alkenyl moiety having from 2 to 6 carbon atoms having atleast one double bond of either E or Z stereochemistry where applicable.The term includes, for example, vinyl, allyl, 1- and 2-butenyl and2-methyl-2-propenyl.

[0061] As used herein the term “divalent (C₂-C₆)alkenylene radical”means a hydrocarbon chain having from 2 to 6 carbon atoms, at least onedouble bond, and two unsatisfied valencies.

[0062] As used herein the term “C₂-C₆ alkynyl” refers to straight chainor branched chain hydrocarbon groups having from two to six carbon atomsand having in addition one triple bond. This term would include forexample, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4hexynyl and5-hexynyl.

[0063] As used herein the term “divalent (C₂-C₆)alkynylene radical”means a hydrocarbon chain having from 2 to 6 carbon atoms, at least onetriple bond, and two unsatisfied valencies.

[0064] As used herein the term “cycloalkyl” means a saturated alicyclicmoiety having from 3-8 carbon atoms and includes, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

[0065] As used herein the term “cycloalkenyl” means an unsaturatedalicyclic moiety having from 3-8 carbon atoms and includes, for example,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyland cyclooctenyl. In the case of cycloalkenyl rings of from 5-8 carbonatoms, the ring may contain more than one double bond.

[0066] As used herein the term “aryl” refers to a mono-or bi-cycliccarbocyclic aromatic group, and to groups consisting of two covalentlylinked mono-or bi-cyclic carbocyclic aromatic groups. Illustrative ofsuch groups are phenyl, biphenyl and napthyl.

[0067] As used herein the unqualified term “heterocyclyl” or“heterocyclic” includes “heteroaryl” as defined below, and in particularmeans a 5-8 membered aromatic or non-aromatic heterocyclic ringcontaining one or more heteroatoms selected from S, N and O, andoptionally fused to a benzyl or second heterocyclic ring, and the termincludes, for example, pyrrolyl, furyl, thienyl, piperidinyl,imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, thiazepinyl, pyrazolyl,pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl,1,4-dihydroquinolyl, 4H-chromenyl, and benzimidazolyl rings.

[0068] As used herein the term “heteroaryl” refers to a 5- or 6-membered aromatic ring containing one or more heteroatoms, andoptionally fused to a benzyl or pyridyl ring; and to groups consistingof (a) two such monocyclic or fused rings which are covalently linked;or (b) one such a monocyclic or fused ring covalently linked to an arylgroup. Illustrative of such groups are thienyl, furyl, pyrrolyl,imidazolyl, benzimidazolyl, thiazolyl, pyrazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,4(([1,2,3]-thiadiazoly4-yl)phenyl and 5-isoxazol-3-ylthienyl.

[0069] As used herein the unqualified term “carbocyclyl” or“carbocyclic” refers to a 5-8 membered ring whose ring atoms are allcarbon.

[0070] Unless otherwise specified in the context in which it occurs, theterm “substituted” as applied to any moiety herein means substitutedwith up to four substituents, each of which independently may be(C₁-C₆)alkyl, phenyl, benzyl, (C₁-C₆)alkoxy, phenoxy, hydroxy, mercapto,(C₁-C₆)alkylthio, amino, halo (including fluoro, chloro, bromo andiodo), trifluoromethyl, cyano, nitro, oxo, —COOH, —CONH₂, —COR^(A),—COOR^(A), —NHCOR^(A), —CONHR^(A), —NHR^(A), —NR^(A)R^(B), or—CONR^(A)R^(B) wherein R^(A) and R^(B) are independently a (C₁-C₆)alkylgroup. In the case where “substituted” means substituted by benzyl, thephenyl ring thereof may itself be substituted with any of the foregoing,except phenyl or benzyl.

[0071] There are at least two actual or potential chiral centres in thecompounds according to the invention because of the presence ofasymmetric carbon atoms. The presence of several asymmetric carbon atomsgives rise to a number of diastereoisomers with R or S stereochemistryat each chiral centre. The invention includes all such diastereoisomersand mixtures thereof. Currently, the preferred stereoconfiguration ofthe carbon atom carrying the R₂ group is R; that of the carbon atomcarrying the R₁ group (when asymmetric) is R.

[0072] In the compounds of formula (I) and (IA) as defined above:

[0073] when Z is a radical of formula —N(OH)CH(═O) R₁ is hydrogen,methyl or trifluoromethyl. When Z is a radical of formula —N(OH)CH(═O),R₁ is hydrogen, methyl, trifluoromethyl, hydroxy or amino. Hydrogen iscurrently preferred in both cases.

[0074] R₂ may be, for example:

[0075] optionally substituted C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynylor cycloalkyl;

[0076] phenyl(C₁-C₆ alkyl)-, phenyl(C₃-C₆ alkenyl)- or phenyl(C₃-C₆alkynyl)- optionally substituted in the phenyl ring;

[0077] cycloalkyl(C₁-C₆ alkyl)-, cycloalkyl(C₃-C₆ alkenyl)- orcycloalkyl(C₃-C₆ alkynyl)- optionally substituted in the cycloalkylring;

[0078] heterocyclyl(C₁-C₆ alkyl)-, heterocyclyl(C₃-C₆ alkenyl)- orheterocyclyl(C₃-C₆ alkynyl)- optionally substituted in the heterocyclylring; or

[0079] CH₃(CH₂)_(p)O(CH₂)_(q)— or CH₃(CH₂)_(p)S(CH₂)_(q)—, wherein p is0, 1, 2 or 3 and q is 1, 2 or 3.

[0080] Specific examples of R₂ groups include

[0081] methyl, ethyl, n- and iso-propyl, n- and iso-butyl, n-pentyl,iso-pentyl 3-methyl-but-1-yl, n-hexyl, n-heptyl, n-acetyl, n-octyl,methylsulfanylethyl, ethylsulfanylmethyl, 2-methoxyethyl, 2-ethoxyethyl,2-ethoxymethyl, 3-hydroxypropyl, allyl, 3-phenylprop-3-en-1-yl,prop-2-yn-1-yl, 3-phenylprop-2-yn-1-yl,3-(2-chlorophenyl)prop-2-yn-1-yl, but-2-yn-1-yl, cyclopentyl,cyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl,cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, furan-2-ylmethyl,furan-3-methyl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-ylmethyl,phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl,4-methoxyphenylpropyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl, and4-methoxybenzyl.

[0082] Presently preferred groups at R₂ are n-propyl, n-butyl, n-pentyl,and cyclopedtylmethyl.

[0083] R₃ may be, for example, hydrogen, methyl, ethyl or benzyl.Hydrogen is presently preferred.

[0084] R₄ may be, for example, a mono- or bicyclic- aryl or heterocyclicring system such as phenyl, furanyl, pyrrolyl, thienyl, naphthyl,1,4-dihydroquinolyl, quinolinyl, isoquinolinyl, cinnolinyl, imidazolyl,indolyl, thiazolyl, tetrazolyl, oxazolyl, 4H-chromenyl or chromenyl; anyof which may be substituted as specified in the definition of R above,for example by methyl, trifluoromethyl, phenyl, cyclohexyl, cyclopentyl,amino, hydroxy, chloro, nitro, oxo, piperidinyl, furanyl, pyrrolyl,thienyl or (particularly in the case of a phenyl ring or a fused benzenering) by methylenedioxy.

[0085] When R₄ is a radical of formula —(CR₅R₆)—Y—R₇, R₅ and R₆ may behydrogen and R₇ may be any of those groups listed above for R₄.

[0086] Specific examples of compounds within or for use within the scopeof the invention include those of the Examples herein:

[0087] Compounds of the invention wherein Z is a radical of formula—N(OH)CH(═O) may be prepared by deprotection of a compound of formula(II) or its sulfonyl analogue

[0088] wherein P represents a hydroxy protecting group, and R₁, R₂, R₃and R₄, are as defined in relation to formula (II). Compounds of formula(II) may be prepared by coupling an amine of formula (III),

[0089] with an acid of formula (I) wherein B is —(C═O)— or —(SO₂)— or anactivated derivative thereof such as an acyl or sulfonyl chloride, usingstandard peptide coupling methods.

[0090] Compounds of formula (III) may be prepared by N-formylation, forexample using formic acetic anhydride, or 1-formylbenzotriazole, ofcompounds of formula (IIIA)

[0091] Wherein P and P′ represent hydroxy and amino protecting groupsrespectively, followed by removal of the amino protecting group P′.

[0092] Hydroxamate compounds of formula (I) for use in accordance withthe invention may be prepared by reacting a compound of formula (V) orthe sulfonyl analogue thereof, or a carboxyl-activated derivativethereof

[0093] with hydroxylamine or an N- and/or O-protected hydroxylamine, andthereafter removing any O- or N-protecting groups. Carboxyl-activatedderivatives of compound (V) include 1-hydroxybenzotriazole ester andpentafluorophenyl ester. A compound of formula (V) may be prepared bystandard peptide coupling methods from an amine of formula (VI),

[0094] wherein P is as defined in relation to formula (II), and an acidof formula (IV), followed by removal of P.

[0095] Intermediates of type (III), (IIIA), (IV) and (VI) are eithercommercially available or accessible by known chemistry fromcommercially available precursors. Further details of the syntheticroutes available for use in the synthesis of the compounds with whichthe invention is concerned are given in the Examples herein.

[0096] Antibacterial or antiprotozoal compositions with which theinvention is concerned may be prepared for administration by any routeconsistent with the pharmacokinetic properties.,of the activeingredient(s).

[0097] Orally administrable compositions may be in the form of tablets,capsules, powders, granules, lozenges, liquid or gel preparations, suchas oral, topical, or sterile parenteral solutions or suspensions.Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants for example potato starch, or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

[0098] For topical application to the skin, the active ingredient(s) maybe made up into a cream, lotion or ointment. Cream or ointmentformulations which may be used for the drug are conventionalformulations well known in the art, for example as described in standardtextbooks of pharmaceutics such as the British Pharmacopoeia.

[0099] The active ingredient(s) may also be administered parenterally ina sterile medium. Depending on the vehicle and concentration used, thedrug can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. Intra-venous infusionis another route of administration for the compounds used in accordancewith the invention.

[0100] Safe and effective dosages for different classes of patient andfor different disease states will be determined by clinical trial as isrequired in the art. It will be understood that the specific dose levelfor any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

[0101] Specific examples of compounds of the invention include thefollowing (where these compounds are N-formyl hydroxylamine derivatives,the corresponding hydroxamic acid analogues are also specific examplesof compounds of the invention. Correspondingly where these compounds arehydroxamic acids the equivalent N-formyl hydroxylamine derivatives arealso specific examples of compounds of the invention) examples 1-19.

[0102] The following abbreviations have been used throughout DICN,N-Dicyclohexylcarbodiimide DIEA Diisopropylethylamine DMAPN,N-Dimethylaminopyridine DMF Dimethylformamide DPPA Diphenylphosphorylazide ESMS Electrospray mass spectroscopy HOAt1-Hydroxy-7-aza-benzotriazole HOBt 1-Hydroxy-7-benzotriazole HPLC Highperformance liquid chromatography LRMS Low resolution mass spectrometryNMR Nuclear Magnetic Resonance PyAOP7-Azabenzotriazol-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate RT Retention time TBAF Tetra-n-butyl ammoniumfluorid TFA Trifluoroacetic acid THF Tetrahydrofuran

[0103]¹H and ¹³Cspectra were recorded using a Bruker DPX 250spectrometer at 250.1 MHz (62.5 MHz for the ¹³C) and a Bruker AMX 500spectometer at 500 MHz (125 MHz for the 3 Mass spectra were obtainedusing a Perkin Elmer Sciex API 165. Analytical HPLC was run on a BeckmanSystem Gold, using Waters Symmetry C18 column (50 mm, 4.6 mm) with 20 to90% solvent B gradient (1.5 ml/min) as the mobile phase. [Solvent Å:0.05% TFA in 10% MeCN 90% water, Solvent B: 0.05% TFA in 10% water 90%MeCN, 5 min gradient time], detection wavelength at 220 or 214 nm.Preparative HPLC was run on a Gilson autoprep instrument using a C18Waters delta pak (15 □m, 300 Å, 25 mm, 10 mm) with 20 to 90% solvent Bgradient as the mobile phase at a flow rate of 15 ml/min. [Solvent A 10%MeCN/water; Solvent B: 10% water/MeCN, 13 min gradient time], UVdetection was at 220 or 214 nm. Reagents were purified and dried wherenecessary by standard techniques.

EXAMPLE 1N-{1R-[(Formyl-hydroxy-amino)-methyl]-pentyl}2-naphthalen-1-yl-acetamide

[0104]

[0105] The title compound was prepared as detailed below (see Scheme 1)from 2R-[(Benzyloxy-formylamino)-methyl]-hexanoic acid, the synthesis ofwhich has been described in WO 99/39704.

[0106] Reagents and conditions: A. DPPA, Et₃N, trimethylsilyl ethanol,toluene; B. TBAF, THF; C. PyAOP, HOAt, Et₃N, CH₂Cl₂; D. EtOH, H₂(g).

Step A: {1R-[(Benzyloxy-formyl-amino)-methyl]-pentyl}-carbamic acid2-trimethylsilanyl-ethyl ester

[0107] To a solution of 2R-[(benzyloxy-formylamino)-methyl]-hexanoicacid (0.5 g, 1.8 mmol) in toluene was added DPPA (379 μl, 1.8 mmol), andtriethylamine (248 μl, 1.8 mmol). The reaction mixture was stirred at80° C. under reflux for 0.5 h. Trimethylsilyl ethanol (516 μl, 3.6 mmol)was then added and the reaction mixture was stirred at 80° C. underreflux for 18 h. The mixture was allowed to cool and the solvent removedin vacuo to yield a clear oil. The residue was purified by flashchromatography (4:1, hexanes:ethyl acetate) to yield the title compoundas a clear oil (882 mg, 62%). ¹H-NMR; δ (CDCl₃, rotamers) 8.19 (1H, brs,CHO), 7.34 (5H, s, ArH), 4.83 (2H, brs), 4.72 (1H, brs), 4.13-4.10 (2H,m), 3.94 (1H, brm), 3.77 (1H, brm), 3.43 (1H, brm), 1.44-1.25 (6H, m),0.93 (2H, t, J=8.5 Hz), 0.86-0.84 (3H, m), 0.00 (9H, s); LRMS: +ve ion417 [M+Na, 100%]. HPLC RT: 7.0 min (100% @220 nm)

Step B: N-(2R-Amino-hexyl)-N-benzyloxy-formamide

[0108] To {1R-[(benzyloxy-formyl-amino)-methyl]-pentyl}carbamic acid2-trimethylsilanyl-ethyl ester (200 mg, 0.51 mmol) was added a 1Msolution of TBAF in THF (2.0 ml, 2.0 mmol), under a blanket of argon.The reaction mixture was stirred for 0.5 h at 50° C. and was thenallowed to cool. The solvent was removed in vacuo, the resulting yellowoil was taken up in dichloromethane (20 ml), was washed with brine (1×20ml), dried (anhydrous magnesium sulphate) and the solvent was evaporatedto yield a clear oil, which was puirifed by flash chromatography (0.1Mammonia solution in MeOH 3%/dichloromethane) to yield the title compoundas a white solid (98 mg, 77%). ¹H-NMR; δ (CDCl₃, rotamers). 8.13 (0.7H,d, J=1.2 Hz), 8.00 (0.3H, d, J=11.9 Hz), 7.36-7.27 (5H, m, ArH),5.75-5.71 (2H, m, NH₂), 4.69 (1.4H, s), 4.67 (0.6H, s), 4.22-4.09 (0.7H,m), 3.68-3.53 (0.3H, m), 3.11-2.65 (2H, m), 1.56-1.25 (6H, m), 0.92-0.86(3H, m); LRMS +ve ion 251 [M+1, 100%], 273 [M+Na, 60%], HPLC RT: 4.5 min(100% @220nm)

Step C: N-{1R-[(Benzyloxy-formyl-amino)-methyl]-pentyl}2-naphthalen-1-yl-acetamide

[0109] To a solution of N-(2R-amino-hexyl)-N-benzyloxy-formamide indichloromethane (5 ml) was added 1-naphthyl acetic acid (70 mg, 0.38mmol), PyAOP (232 mg, 0.45 mmol), HOAt (5 mg, 34.4 μmol) andtriethylamine (95 μl, 0.69 mmol), the reaction mixture was stirred for18 h at room temperature. The solvent was removed in vacuo and the crudeyellow oil was taken up in ethyl acetate (30 ml) and was washed with 1Mhydrochloric acid (1×30 ml), 1M sodium carbonate (1×30 ml), brine (1×30ml), dried (anhydrous magnesium sulphate) and the solvent removed invacuo to yield a clear oil, which was purified by flash chromatography(3.5% methanol/dichloromethane) to yield the title compound as a clearoil (86 mg, 60%). ¹H-NMR; δ (CDCl₃, rotamers). 7.93-7.73 (4H, m, ArH,CHO), 7.50-7.24 (9H, m, ArH), 5.95 (1H, brs, NH), 4.88 (2H, dd, J=27.3Hz & 10.8 Hz), 4.36 (1H, brs), 4.16-3.95 (3H, m), 3.46 (1H, dd, J=14.8Hz & 4.4 Hz), 1.39-1.15 (6H, m), 0.85-0.81 (3H, m). LRMS +ve ion 419(M+1, 40%), 441 (M+Na, 50%), HPLC RT: 6.5 min (100% @220 nm)

Step D: N-{1R-[(Formyl-hydroxy-amino)-methyl]-pentyl}-2-naphthalen-1-yl-acetamide

[0110] To a solution of N{1R-[(benzyloxy-formyl-amino)-methyl]-pentyl]-2-naphthalen-1-yl-acetamide(86 mg, 0.20 mmol) in ethanol (5 ml), under a blanket of argon, wasadded 10% palladium on charcoal (10 mg) and a few drops of formic acid.Hydrogen was bubbled through the suspension for 1 hour and then thereaction was stirred under an atmosphere of hydrogen for 60 hours. Thepalladium catalyst was filtered off and the solvent removed in vacuo toyield a clear oil (60 mg) which was impure. The residue was purified bypreparative HPLC to yield the title compound as a white solid (40 mg,60%).

[0111]¹H-NMR; δ (CDCl₃), 8.99 (1H, s, CHO), 7.87 (1H, d, J=8.1 Hz),7.81-7.77 (2H, m, ArH), 7.52-7.39 (3H, m, ArH), 7.28-7.25 (1 H, m, ArH),6.20 (1 H, d, J=8.5 Hz, NH), 4:25(1H, d, J=16.6 Hz), 4.124.00 (2H, m),3.99-3.91 (1H, m), 2.97 (1H, dd, J=2.8 Hz & 13.3 Hz), 1.45-1.00 (6H, m),0.85 (3H, t, J=7.2 Hz); ¹³C-NMR; δ (CDCl₃), 14.2, 22.6, 28.5, 30.5,36.7, 46.0, 50.9, 124.4, 125.9, 126.1, 128.1 (2c), 128.8, 129.1, 132.4,132.8, 134.1, 164.0, 172.6; LRMS: +ve ion 329(M+1, 40%), 352 (M+Na,100%), -ve ion 327(M−1, 100%) HPLC: RT 5.9 min (100% @220 nm).

[0112] Examples 2-5 were prepared from the common intermediate as shownin Scheme 2. The acid chloride of each right hand side fragment was usedas the coupling partner rather than tradition coupling reagents. Theacid chlorides were formed form the corresponding acid using thionylchloride. These compounds were not isolated and were used directly inthe coupling step (Scheme 2).

Step A: {1R-[(Benzyloxy-formyl-amino)-methyl]-pentyl}carbamic acidbenzyl ester

[0113] To a solution of 2R-[(Benzyloxy-formylamino)-methyl]-hexanoicacid (7.4 g, 26.5 mmol) in toluene (80 ml) was added DPPA (5.6 ml, 26.5mmol), and triethylamine (3.7 ml, 26.5 mmol). The reaction mixture wasstirred at 80° C. under reflux for 1 h. benzyl alcohol (5.7 ml, 53 mmol)was then added and the reaction mixture was stirred at 80° C. underreflux for 18 h. The mixture was allowed to cool and the solvent removedin vacuo to yield a clear oil. The residue was purified by flashchromatography (4:1, hexanes:ethyl acetate gradient to 1:1 hexanes:ethylacetate) to yield the title compound as a clear oil (5.5 g, 54%).Compound was used directly in the next step without furtherpurification. LRMS: +ve ion 385 (M+1), 407 (M+Na); HPLC RT: 6.5 min (80%@220 nm).

Step B: N-(2R-amino-hexyl)-N-hydroxy-formamide

[0114] To a solution ofN-{1R-[(benzyloxy-formyl-amino)-methyl]-pentyl}2-naphthalen-1-yl-acetamide(5.5 g, 14.3 mmol) in ethanol (60 ml), under a blanket of argon, wasadded 10% palladium on charcoal (550 mg) in a slurry of EtOH (10 ml).Hydrogen was bubbled through the suspension for 2.5 h and then thereaction was stirred under an atmosphere of hydrogen for 60 hours. Thepalladium catalyst was filtered off and the solvent removed in vacuo toyield a clear oil (60 mg.) which was impure. The residue was purified bypreparative HPLC to yield the title compound as a white solid (40 mg,60%). LRMS: +ve ion: 161 (M+1).

Step C:5-ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5]quinoline-7-carboxylic acidchloride

[0115] To a solution of5-ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5]quinoline-7-carboxylic acid(245 mg, 0.94 mmol) in dichloromethane (3 ml) was added thionyl chloride(2 ml) and the reaction mixture was stirred at 80° C. for 4 h. Themixture was allowed to cool and the solvent was removed in vacuo. Thecrude acid chloride was used directly in the coupling step withoutfurther purification.

Step D:5-Ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5]quinoline-7-carboxylic acid{1R-[(formyl-hydroxy-amino)-methyl]-pentyl}-amide.

[0116] To a solution of5-ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5]quinoline-7-carboxylic acidchloride (isolated crude from previous reaction) in dichloromethane (5ml) was added a solution of N-(2R-amino-hexyl)-N-hydroxy-formamide (60mg, 0.38 mmol) in dichloromethane (5 ml) followed by DIEA resin (1.44 g,3.9 mmol/g), the suspension was stirred at room temperature for 24 h.Aminomethyl polystyrene resin (1.0 g, 1.5 mmol/g) was then added to thereaction mixture and the reaction mixture was stirred for a further 60h. The resins were filtered and washed with dichloromethane (3×5 ml andmethanol (3×5 ml), the filtrate was combined and the solvent was removedin vacuo to yield an impure oil. Preparative HPLC yielded the titlecompound (3.5 mg) as an oil. See table 1 for characterisation data.

[0117] Examples 2-5 were prepared in a manner analogous to example 1.Characterisation data for these compounds is shown in table 1. Alsoshown is there inhibition of the PDF E. coli (Ni) enzyme. TABLE 1 E coliPDF (Ni) HPLC Example Structure BB NUMBER (nM) RT (min) MS 2

85138 30 5.6 min (95%) 404(M + 1) 426(M + Na) 3

85140 60 6.2 min (95%) 414(M + 1) 436(M + Na) 4

85151 20 6.1 min (100%) 416(M + Na) 5

85152 200 5.8 min (96%) 332(M + 1) 355(M + Na) 331(M − 1)

[0118] 2.5-Ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5]quinoline-7-carboxylic acid{1R-[(formyl-hydroxy-amino)-methyl]-pentyl}amide.

[0119] 3. 1-Cyclohexyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid{1R[(formyl-hydroxy-amino)-methyl]-pentyl}-amide.

[0120] 4. 6-Chloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid{1R[(formyl-hydroxy-amino)-methyl]-pentyl}-amide.

[0121] 5. 4-Oxo-4H-chromene-3-carboxylic acid{1R-[(formyl-hydroxy-amino)-methyl]-pentyl}amide.

EXAMPLE 6 3-(Naphthalene-1-sulfonylamino)-hexanoic acid hydroxyamide

[0122]

[0123] The title compound was prepared as described below:

[0124] Reagents and conditions: A. Fmoc-β-3-aminohexanoic acid, HOBT,DIC, DMF, O/N; B. 20% piperazine, DMF, 5 h; C. (I) methyl trimethylallyl dimethyl ketone acetal, DMAP, 1-naphthalene sulphonylchloride,CH₂Cl₂ and (ii) 1:9:10 Trimethyl silane/trifluoroacetic acid/CH₂Cl₂; D.(I) DIC, 5-methoxy-2-methyl-3-indole acetic acid , DMF and (ii) 1:9:10Trimethyl silane/trifluoroacetic acid/CH₂Cl₂

[0125] Note: For the preparation of Wang modified resin see C. Floyd etal., Tetrahedron Left., 1996, 37, 8045.

Step A: Fmoc-beta-3-aminohexanoyl-p-benzyloxybenzyl alcohol resinhydroxamate

[0126] To a solution of Fmoc-β-3aminohexanoic acid (2.12 g, 6.0 mmol),HOBT (0.81 g, 6.0 mmol) and DIC (0.67 ml, 6.0 mmol) in DMF (20 ml) wasadded p-benzyloxybenzyl alcohol resin (2.0 g, 2.0 mmol). The reactionmixture was shaken overnight. The resin was filtered and washed with DMF(3×10 ml). The resin was then washed with MeOH (10 ml) followed bydichloromethane (10 ml) and this process was repeated three times. Theresin was dried overnight under reduced pressure.

Step B: Beta-3-aminohexanoyl-p-benzyloxybenzyl alcohol resin hydroxamate

[0127] A 20% solution of piperazine in DMF (20 ml) was added toFmoc-β-3-aminohexanoyl-p-benzyloxybezyl alcohol resin hydroxamate (2.59g, 2 mmol). The reaction mixture was shaken for 5 hours. The resin wasfiltered and washed with DMF (3×10 ml). The resin was then washed withMeOH (10 ml) followed by dichloromethane (10 ml) and this process wasrepeated three times. The resin was dried overnight under reducedpressure.

Step C: 3-(Naphthalene-1-sulfonylamino)-hexanoic acid hydroxyamide

[0128] (i) A solution of methyl trimethyl allyl dimethyl ketone acetal(304 μl, 1.5 mmol) and DMAP (3.8 mg, 0.03 mmol) in dichloromethane (3ml) was added to β-3-aminohexanoyl-p-benzyloxybenzyl alcohol resinhydroxamate (150 mg, 0.15 mmol) followed by the addition of1-naphthalene sulphonylchloride (340 mg, 1.5 mmol). The reaction mixturewas shaken overnight. The resin was filtered and washed with DMF (3×10ml). The resin was then washed with MeOH (10 ml) followed bydichloromethane (10 ml) and this process was repeated three times. Theresin was dried overnight under reduced pressure.

[0129] (ii) A solution of 1:4:5 trimethylsilane/trifluoroaceticacid/dichloromethane (3 ml) was added to3-(Naphthalene-1-sulfonylamino)-hexanoyl-p-benzyloxybenzyl alcohol resinhydroxamate (170 mg, 0.15 mmol). The reaction mixture was stirredoccasionally over 45 minutes. The solution was collected by filtrationand the resin washed with a solution of 1:4:5trimethylsilane/trifluoroacetic acid/dichloromethane (2 ml) anddichloromethane (3 ml). The solvents were removed under reduced pressureand the residue was purified by preparative HPLC. The title compound wasobtained as a clear oil (1.9 mg, 4%). Characterisation data is providedin Table 2.

Step D: 3-[2-(5-Methoxy-2-methyl-1H-indol-3-yl)-acetylamino]-hexanoicacid hydroxyamide

[0130] (i) To a solution of 5-methoxy-2-methyl-3-indole acetic acid (98mg, 0.45 mmol) and DIC (70 □l, 0.45 mmol) in DMF, was addedβ-3-[2-(5-methoxy-2methyl-1H-indol-3-yl)-acetylamino]-hexanoyl-p-benzyloxybenzylalcohol resin hydroxamate. The reaction mixture was shaken overnight.The resin was filtered and washed with DMF (3×10 ml) once followed bywashes with MeOH (10 ml) then dichloromethane (10 ml) repeated threetimes. The resin was dried overnight under reduced pressure.

[0131] (ii) A solution of 1:4:5 trimethylsilane/trifluoroaceticacid/dichloromethane (3 ml) was added toβ-3-[2-(5-methoxy-2-methyl-1H-indol-3-yl)-acetylamino]-hexanoyl-p-benzyloxybenzylalcohol resin hydroxamate (170 mg, 0.15 mmol). The reaction mixture wasstirred occasionally over 45 min. The solution was collected byfiltration and the resin washed with a solution of 1:4:5 trim thylilane/trifluoroacetic acid/dichloromethane (2 ml) and dichloromethane (3ml). The solvent were removed under reduced pressure and the residue waspurified by preparative HPLC. The title compound was obtained as a clearoil (11.8 mg, 22%). Characterisation data is provided in Table 2.

[0132] The compounds of Examples 6-19 were prepared by the syntheticroute outlined in Scheme 2 and as described in detail for Example 6.Examples 7 8, 13, 14 and 15 were prepared as in scheme 3 but followingStep C. Examples 9-12 and 16-19 were prepared as in scheme 3 butfollowing Step D. Note: Examples 13-19 were prepared in a identicalmanner as shown in scheme 2 but utilising the starting materialL-homoisoleucine. Compounds 6-19 were purified by preparative HPLC.TABLE 2 Prep HPLC ES-MS Retention Example Structure Ions Seen Time(mins) 6

M + Na = 359 M − 1 = 335 10.8 7

M + Na = 367 M − 1 = 343 9.2 8

M + Na = 377 M − 1 = 353 11.3 9

M + 1 = 348 M − 1 = 346 9.6 10

M + Na = 368 M − 1 = 344 10.3 11

M + Na = 337 M − 1 = 313 10.7 12

M + Na = 341 M − 1 = 317 10.1

[0133] Examples 7-12 are named as follows:

EXAMPLE 7 3-(Benzo[1,2,5]thiadiazole4-sulfonylamino)-hexanoic acidhydroxyamide EXAMPLE 8 3-(3,4Dichloro-benzenesulfonylamino)-hexanoicacid hydroxyamide EXAMPLE 9 3-[2-(5-Methoxy-2-methyl-1H-indol-3-yl)-acetylamino]-hexanoic acid hydroxyamide EXAMPLE 103-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-acetylamino]-hexanoic acidhydroxyamide EXAMPLE 11 3-(2-Naphthalen-1-yl-acetylamino)-hexanoic acidhydroxyamide EXAMPLE 12 4-Oxo-4H-chromene-3-carboxylic acid(1-hydroxycarbamoylmethyl-butyl)-amide

[0134] TABLE 3 Prep HPLC ES-MS Retention Example Structure Ions SeenTime (mins) 13

M + Na = 373 M − 1 = 349 11.1 14

M + Na = 381 M − 1 = 357 9.6 15

M + Na = 391 M − 1 = 369 11.6 16

M + 1 = 316 M − 1 = 314 10.3 17

M + H = 362 M + Na = 384 M − 1 = 3360 9.8 18

M + Na = 337 M − 1 = 313 10.14 19

M + Na = 351 M − 1 = 327 10.9

[0135] Examples 13-19 are named as follows:

EXAMPLE 13 4S-Methyl-3R-(naphthalene-1-sulfonylamino)-hexanoic acidhydroxyamide EXAMPLE 143R-(Benzo[1,2,5]thiadiazole4S-sulfonylamino)-methyl-hexanoic acidhydroxyamide EXAMPLE 153R-(3,4-Dichloro-benzenesulfonylamino)4S-methyl-hexanoic acidhydroxyamide EXAMPLE 163R-(Isoquinoline-1-sulfonylamino)4S-methyl-hexanoic acid hydroxyamideEXAMPLE 173R-[2-(5-Methoxy-2-methyl-1H-indol-3-yl)-acetylamino]4S-methyl-hexanoicacid hydroxyamide EXAMPLE 184S-Methyl-3R-[2-(5-methyl-2-phenyl-oxazol4-yl)-acetylamino]-hexanoicacid hydroxyamide EXAMPLE 194S-Methyl-3R-(2-naphthalen-1-yl-acetylamino)-methyl-hexanoic acidhydroxyamide BIOLOGICAL EXAMPLE

[0136] The susceptibilities of strains of bacteria to the compound ofExample 1 were determined by a standard agar plate dilution methodfollowing recommendations in British Society for AntimicrobialChemotherapy Working Party. 1991, “A guide to sensitivity testingBritish Society for Antimicrobial Chemotherapy, London, United Kingdom”.Briefly, Iso-Sensitest agar (pH 7.2: Oxoid, United Kingdom) is employed,supplemented with 5% horse blood (Oxoid) and 20 μg of NAD (Sigma) per mlare added to support growth of fastidious bacteria. The inoculum used isapproximately 10⁴ colony forming units of each isolate contained in avolume of 1 μl. Plates are incubated 18 to 24 hr in air, or forfastidious bacteria an atmosphere enriched with 4-6% carbon dioxide at35° C. The MIC is determined as the lowest concentration of anAntimicrobial tested that inhibited growth of the inoculum, disregardinga single persisting colony or faint haze caused by the inoculation.

[0137] The MICs of the compound against 3 test strains of Haemophiliainfluenza were in the range 0.5- 2 μg/ml.

1. The use of a compound of formula (I) or (IA) or a pharmaceutically orveterinarily acceptable salt, hydrate or solvat thereof in thepreparation of a composition for treatment of bacterial or protozoalinfections in humans and non-human mammals:

wherein: Z represents a radical of formula —N(OH)CH(═O) or of formula—C(═O)NH(OH); R₁ represents hydrogen, methyl or trifluoromethyl, or,except when Z is a radical of formula —N(OH)CH(═O), a hydroxy or aminogroup; R₂ represents a radical of formula R₁₀—(X)_(n)-(ALK)_(m)— whereinR₁₀ represents hydrogen, or a C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,cycloalkyl, aryl, or heterocyclyl group, any of which may beunsubstituted or substituted by (C₁-C₆)alkyl, (C₁-C₆)alkoxy, hydroxy,mercapto, (C₁-C₆)alkylthio, amino, halo (including fluoro, chloro, bromoand iodo), trifluoromethyl, cyano, nitro, oxo, —COOH, —CONH₂, —COOR^(A),—NHCOR^(A), —NR^(A)COR^(B), —CONHR^(A), —NHR^(A), —NR^(A)R^(B), or—CONR^(A)R^(B) wherein R^(A) and R^(B) are independently a (C₁-C₆)alkylgroup or R^(A) and R^(B) taken together with the atom(s) to which theyare attached form a 5, 6 or 7 membered ring and ALK represents astraight or branched divalent C₁-C₆ alkylene, C₂-C₆ alkenylene, or C₂-C₆alkynylene radical, and may be interrupted by one or more non-adjacent—NH—, —O— or —S— linkages, X represents —NH—, —O— or —S—, and m and nare independently 0 or 1; R₃ represents hydrogen, C₁-C₆alkyl, or benzyl;R₄ represents (i) aryl, heterocyclic, aryl(C₁-C₆alkyl)-, orheterocyclic(C₁-C₆alkyl)-, any of which may be unsubstituted orsubstituted by cycloalkyl, nonaromatic heterocyclyl, methylenedioxy orany of the substituents defined as permitted in R₁₀; or (ii) a radicalof formula —(CR₅R₆)—Y—R₇ wherein R₅ represents hydrogen, C₁-C₆alkyl,C₂-C₆alkenyl, C₁-C₆alkynyl, aryl, heteroaryl, cycloalkyl,aryl(C₁-C₆alkyl)- or heteroaryl(C₁-C₆alkyl)-, any of which may beunsubstituted or substituted by or any of the substituents defined aspermitted in R₁₀ R₆ represents hydrogen or fluoro, R₇ represents aryl,heteroaryl, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂ or C₁-C₆alkyl, any of whichmay be unsubstituted or substituted by cycloalkyl, non-aromaticheterocyclyl, methylenedioxy or any of the substituents defined aspermitted in R₁₀, and Y represents —(CH₂)—, —C(═O)—, —C(=S)— or—C(=N—OR₈)— wherein R₈ represents C₁-C₆ alkyl or benzyl.
 2. A method forthe treatment of bacterial or protozoal infections in humans andnon-human mammals, which comprises administering to a subject sufferingsuch infection an antibacterially or antiprotozoally effective dose of acompound of formula (I) as defined in claim
 1. 3. A compound of formula(I) as set forth in claim 1 or a pharmaceutically or veterinarilyacceptable salt, hydrate or solvate thereof, wherein Z represents aradical of formula —N(OH)CH(═O), and R₄ represents (a) aryl orheterocyclic, either of which may be unsubstituted or substituted bycycloalkyl, non-aromatic heterocyclyl, methylenedioxy or any of thesubstituents defined as permitted in R₁₀; or (b) aryl(C₁-C₆alkyl)- orheterocyclic(C₁-C₆alkyl)-, either of which may be unsubstituted orsubstituted by cycloalkyl, non-aromatic heterocyclyl, methylenedioxy orany of the substituents defined as permitted in R₁₀ EXCEPT THAT the—(C₁-C₆alkyl)- radical in the aryl(C₁-C₆alkyl)- orheterocyclic(C₁-C₆alkyl)- group may not be substituted by oxo; or (c) aradical of formula —(CR₅R₆)—Y—R₇ wherein R₅ represents hydrogen,C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆alkynyl, aryl, heteroaryl, cycloalkyl,aryl(C₁-C₆alkyl)- or heteroaryl(C₁-C₆alkyl)-, any of which may beunsubstituted or substituted by or any of the substituents defined aspermitted in R₁₀ R₆ represents hydrogen or fluoro, R₇ represents aryl,heteroaryl, or C₁-C₆alkyl, any of which may be unsubstituted orsubstituted by cycloalkyl, non-aromatic heterocyclyl, methylenedioxy orany of the substituents defined as permitted in R₁₀, and Y represents—(CH₂)—, —C(═O)—, —C(═S)— or —C(=N—OR₈)— wherein R₈ represents C₁-C₆alkyl or benzyl; or (d) a radical of formula —(CR₅R₆)—Y—R₇ wherein R₅represents hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₁-C₆alkynyl, aryl,heteroaryl, cycloalkyl, aryl(C₁-C₆alkyl)- or heteroaryl(C₁-C₆alkyl)-,any of which may be unsubstituted or substituted by or any of thesubstituents defined as permitted in R₁₀ R₆ represents hydrogen orfluoro, R₇ represents —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂ either of whichmay be unsubstituted or substituted by cycloalkyl, non-aromaticheterocyclyl, methylenedioxy or any of the substituents defined aspermitted in R₁₀ and Y represents a bond, —(CH₂)—, —C(═O)—, —C(═S)— or—C(═N—OR₈)— wherein R₈ represents C₁-C₆ alkyl or benzyl PROVIDED THATwhen R₆ is hydrogen then Y is not —C(═O)—.
 4. A use as claimed in claim1, a method as claimed in claim 2, or compound as claimed in claim 3wherein R₁ is hydrogen.
 5. A use as claimed in claim 1, a method asclaimed in claim 2, or compound as claimed in claim 3 wherein R₂ is:optionally substituted C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl orcycloalkyl; phenyl(C₁-C₆ alkyl)-, phenyl(C₃-C₆ alkenyl)- or phenyl(C₃-C₆alkynyl)- optionally substituted in the phenyl ring; cycloalkyl(C₁-C₆alkyl)-, cycloalkyl(C₃-C₆ alkenyl)- or cycloalkyl(C₃-C₆ alkynyl)-optionally substituted in the cycloalkyl ring; heterocyclyl(C₁-C₆alkyl)-, heterocyclyl(C₃-C₆ alkenyl)- or heterocyclyl (C₃-C₆ alkynyl)-optionally substituted in the heterocyclyl ring; orCH₃(CH₂)_(p)O(CH₂)_(q)— or CH₃(CH₂)_(p)S(CH₂)_(q)—, wherein p is 0, 1, 2or 3 and q is 1, 2 or
 3. 6. A use as claimed in claim 1, a method asclaimed in claim 2, or compound as claimed in claim 3 wherein R₂ ismethyl, ethyl, n- or iso-propyl, n- and iso-butyl, n-pentyl, iso-pentyl,3-methyl-but-1-yl, n-hexyl, n-heptyl, n-acetyl, n-octyl,methylsulfanylethyl, ethylsulfanylmethyl, 2-methoxyethyl, 2-ethoxyethyl,2-ethoxymethyl, 3-hydroxypropyl, allyl, 3-phenylprop-3-en-1-yl,prop-2-yn-1-yl, 3-phenylprop-2-yn-1-yl,3-(2-chlorophenyl)prop-2-yn-1-yl, but-2-yn-1-yl, cyclopentyl,cyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl,cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, furan-2-ylmethyl,furan-3-methyl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-ylmethyl,phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl,4-methoxyphenylpropyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl, or4-methoxybenzyl.
 7. A use as claimed in claim 1, a method as claimed inclaim 2, or compound as claimed in claim 3 wherein R₂ is n-propyl,n-butyl, n-pentyl, or cyclopentylmethyl.
 8. A use as claimed in claim 1,a method as claimed in claim 2, or a compound as claimed in claim 3wherein R₃ is hydrogen.
 9. A use as claimed in claim 1, a method asclaimed in claim 2, or compound as claimed in claim 3 wherein R₄ isphenyl, furanyl, pyrrolyl, thienyl, naphthyl, quinolinyl, isoquinolinyl,cinnolinyl, imidazolyl, indolyl, thiazolyl, tetrazolyl, oxazolyl,quinolyl, 1,4-dihydroquinolyl, 4H-chromenyl or chromenyl, any of whichmay be substituted by methyl, trifluoromethyl, phenyl, amino, hydroxy,chloro, nitro, oxo, piperidinyl, furanyl, pyrrolyl, thienyl or (in thecase of a phenyl ring or a fused benzene ring) by methylenedioxy.
 10. Ause as claimed in claim 1, a method as claimed in claim 2, or compoundas claimed in claim 3 wherein R₄ is a radical of formula —(CR₅R₆)—Y—R₇,R₅ and R₆ are hydrogen, Y is a bond, and R₇ is as defined for R₄ inclaim
 10. 11. A compound as claimed in claim 3 wherein R₁ and R₃ arehydrogen, R₂ is n-propyl, n-butyl, n-pentyl, or cyclopentylmethyl, andR₄ is as defined in claim 9 or claim
 10. 12. A compound of formula 1 asdefined in claim 1 which is specifically named herein, or apharmaceutically or veterinarily acceptable salt, hydrate or solvatethereof.
 13. A pharmaceutical or veterinary composition comprising acompound as claimed in any of claims 3 to 12 together with apharmaceutically or veterinarily acceptable carrier.